The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.
Protein Kinase C's (PKCs) are a family of kinases which phosphorylate serine and threonine residues on a large number of proteins, thereby regulating a number of cellular responses. There are 11 isoforms which are subdivided into classical isoforms including PKC-α, -βI, -βII and -γ, which are diacylglycerol- and calcium-dependent; novel isoforms including PKC-δ, -ε, -η and -θ, which are diacylglycerol-dependent; and atypical isoforms including PKC-λ, ι and -ζ, which are diacylglycerol- and calcium-independent.
Over recent years, the PKC-θ isoform has increasingly been recognized as a promising therapeutic target for various conditions. PKC-θ plays a major role in the function of the immune system through the control of T-cell function. PKC-θ translocates to the nucleus from the cytoplasm where it influences inducible immune responsive gene transcription and microRNAs essential for an effective immune response in T-cells. Dysregulation of PKC-θ has been shown to be involved in inflammatory disorders, tumor progression and metastasis. PKC-θ activity has also been shown to be involved in various neurological, vascular and airway disorders. More recently, PKC-θ dysregulation has been linked to aggressive breast cancers and PKC-θ has been shown to play a role in the induction of epithelial to mesenchymal cell transition (EMT) and formation of breast cancer stem cells (CSCs) (Zafar, et al. (2014) Mol Cell Biol, 34(36): 2961-2980; Lim, et al. (2015) Immunology, 146: 508-522).
Due to the involvement of PKC-θ in inflammatory disorders and tumor formation and progression, PKC-θ is a promising therapeutic target. Whilst there are several PKC-θ inhibitors in development, notably sotrastaurin, which is currently undergoing trials for psoriasis and organ transplantation, these inhibitors typically suffer from a lack of selectivity for PKC-θ over the other PKC enzymes. Due to the large number of cellular responses mediated by the PKC enzymes, selective PKC-θ inhibition is highly desired (Lim, et al. (2015) Immunology, 146: 508-522; Manicassamy (2009) Curr Opin Investig Drugs, 10(11): 1225-1235).
Accordingly, there exists a need for new therapeutic agents that inhibit PKC-θ and which may be useful in conditions associated with PKC-θ overexpression, such as cancer.